Prolyl isomerases in gene transcription

Abstract

Background Peptidyl-prolyl isomerases (PPIases) are enzymes that assist in the folding of newly-synthesized proteins and regulate the stability, localization, and activity of mature proteins. They do so by catalyzing reversible (cis-trans) rotation about the peptide bond that precedes proline, inducing conformational changes in target proteins. Scope of Review This review will discuss how PPIases regulate gene transcription by controlling the activity of (1) DNA-binding transcription regulatory proteins, (2) RNA polymerase II, and (3) chromatin and histone modifying enzymes. Major Conclusions Members of each family of PPIase (cyclophilins, FKBPs, and parvulins) regulate gene transcription at multiple levels. In all but a few cases, the exact mechanisms remain elusive. Structure studies, development of specific inhibitors, and new methodologies for studying cis/trans isomerization in vivo represent some of the challenges in this new frontier that merges two important fields. General Significance Prolyl isomerases have been found to play key regulatory roles in all phases of the transcription process. Moreover, PPIases control upstream signaling pathways that regulate gene-specific transcription during development, hormone response and environmental stress. More broadly, although transcription is often rate-limiting in the production of enzymes and structural proteins, post-transcriptional modifications are also critical, and PPIases play key roles here as well (see other reviews in this issue).

A Slow Conformational Switch in the BMAL1 Transactivation Domain Modulates Circadian Rhythms

“…Proline isomerization has demonstrated roles at each step of transcriptional regulation, from protein folding and regulation of transcription factor interactions, to modification and recognition of histone tails, and conformational control of the RNA Pol II C-terminal domain that controls its activity (reviewed in (Hanes, 2015)). Although we provide evidence in support of a binary conformational switch in the TAD by NMR and its ability to influence circadian timekeeping in cellular reconstitution assays, we still don't understand exactly how the switch regulates circadian period.…”

Cyclophilins and cyclophilin inhibitors in nidovirus replication

“…Cyps are involved in a wide range of cellular processes, including protein folding, protein trafficking, and cell signaling (Naoumov, 2014). Despite the fact that all members of the PPIase superfamily share the same enzymatic activity, protein sequences and structures differ enormously between the three families (Barik, 2006;Davis et al, 2010;Hanes, 2015). The human genome is currently believed to encode 19 cyclophilins, 18 FKBPs, and three parvulins (Pin1, Par14, and Par17) (Gray et al, 2015).…”

Implication of the Whitefly Bemisia tabaci Cyclophilin B Protein in the Transmission of Tomato yellow leaf curl virus

“…Members of the PPIase protein family (e.g., cyclophilins, FKBPs, and parvulins) are enzymes found in both eukaryotes and prokaryotes, participate in cell signaling, gene transcription and assist folding and localization of proteins, respectively (Hanes, 2015). More recently, Cyps were shown to facilitate dissociation of the human Papillomavirus Type 16 L1 and L2 capsid proteins from L2/DNA complexes following virus entry (Bienkowska-Haba et al, 2012), while CypA was shown to bind Tomato bushy stunt tombusvirus and inhibit tombusvirus replicase assembly (Kovalev and Nagy, 2013).…”